Carbidopa, an activator of aryl hydrocarbon receptor, suppresses IDO1 expression in pancreatic cancer and decreases tumor growth

Abstract

IDO1 is an immunomodulatory enzyme responsible for tryptophan catabolism. Its expression in immune cells, especially the DCs, has attracted attention because it leads to tryptophan depletion at the immunological synapse, thereby causing T-cell anergy and immune evasion by the tumor cells. Cancer cells also overexpress IDO1. Immunotherapy targeting IDO1 has been one of the focus areas in cancer biology, but lately studies have identified non-immune related functions of IDO1 leading to a paradigm shift with regard to IDO1 function in the context of tumor cells. In this study, we show that PDAC tissues and PDAC cells overexpress IDO1. The expression level is reciprocally related to overall patient survival. We further show that carbidopa, an FDA-approved drug for Parkinson's disease as well as an AhR agonist, inhibits IDO1 expression in PDAC cells. Using athymic nude mice, we demonstrate that carbidopa-mediated suppression of IDO1 expression attenuates tumor growth. Mechanistically, we show that AhR is responsible for carbidopa-mediated suppression of IDO1, directly as a transcription factor and indirectly by interfering with the JAK/STAT pathway. Overall, targeting IDO1 not only in immune cells but also in cancer cells could be a beneficial therapeutic strategy for PDAC and potentially for other cancers as well and that carbidopa could be repurposed to treat cancers that overexpress IDO1.

Description

© 2022 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). Open access for this article was enabled by the participation of Texas Tech University Health Sciences in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society Center.

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Keywords

Aryl Hydrocarbon Receptor, Carbidopa, Indoleamine Dioxygenase 1, JAK/STAT Signaling, Pancreatic Cancer

Citation

Ksenija Korac, Devaraja Rajasekaran, Tyler Sniegowski, Bradley K. Schniers, Andrew F. Ibrahim, Yangzom D. Bhutia; Carbidopa, an activator of aryl hydrocarbon receptor, suppresses IDO1 expression in pancreatic cancer and decreases tumor growth. Biochem J 16 September 2022; 479 (17): 1807–1824. doi: https://doi.org/10.1042/BCJ20210851

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